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Background and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.Design Double blind randomised trial.Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza.Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.Registration Clinical Trials NCT00298233

Recent studies have found that circular RNAs (circRNAs) play crucial roles not only in the normal growth and the development of different tissues and organs but also in the pathogenesis and progression of various disorders. However, the expression patterns and the function of circRNAs in acute ischemic stroke (AIS) in the South Chinese Han population are unclear. In the present study, RNA sequencing (RNA-seq) data was generated from 3 AIS patients and 3 healthy controls. The circRNAs were detected and identified by CIRI2 and Find_circ software. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were used to detect the expression of circRNAs. Meanwhile, the potential diagnostic value of the selected circRNAs for AIS was assessed by generating receiver operating characteristic (ROC) curve with area under curve (AUC). The bioinformatic analysis of the host genes of differentially expressed (DE) circRNAs was performed by gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, KOBAS for pathway analysis and regulatory network analysis. miRNA-circRNA and miRNA-mRNA interactions were predicted by using TargetScan, miRanda and starBase. CircRNA-miRNA-mRNA interaction networks were created with Cytoscape. Our result showed that there were 2270 DE circRNAs between AIS patients and healthy controls. Among them, 659 were found upregulated and 1611 were downregulated. Bioinformatic analysis showed that the DE circRNAs were related to the following biological processes: endocytosis, energy metabolism, apoptosis, FoxO signaling pathway, platelet activation, neurotrophin signaling pathway and VEGF signaling pathway, which may be associated with the pathological of AIS. Three randomly selected circRNAs were successfully validated by qRT‐PCR. The results show that hsa_circ_0005548 was significantly upregulated, while hsa_circ_0000607 and hsa_circ_0002465 were significantly downregulated in AIS. Furthermore, the AUC values for hsa_circ_005548, hsa_circ_0000607 and hsa_circ_0002465 were 0.51, 0.75 and 0.69, respectively, suggesting that hsa_circ_0000607 and hsa_circ_0002465 could be potential biomarkers for AIS. In addition, Bcl2 was predicted to be a direct target of miR-337-3p, and hsa_circRNA_0000607 was predicted to act as a sponge for miR-337-3p. Thus, hsa_circ_0000607 may be involved in AIS by regulating the miR-337-3p/Bcl2 axis. Collectively, our findings indicate that numerous dysregulated circRNAs may play pivotal functional roles in AIS and hsa_circ_0000607 may play a crucial role in the pathogenesis and progression of AIS by regulating the miR-337-3p/Bcl2 axis.

Prebiotics are food ingredients that improve health by modulating the colonic microbiota. The bifidogenic effect of the prebiotic inulin is well established; however, it remains unclear which species of Bifidobacterium are stimulated in vivo and whether bacterial groups other than lactic acid bacteria are affected by inulin consumption. Changes in the faecal microbiota composition were examined by real-time PCR in twelve human volunteers after ingestion of inulin (10 g/d) for a 16-d period in comparison with a control period without any supplement intake. The prevalence of most bacterial groups examined did not change after inulin intake, although the low G+C % Gram-positive species Faecalibacterium prausnitzii exhibited a significant increase (10·3 % for control period v. 14·5 % during inulin intake, P = 0·019). The composition of the genus Bifidobacterium was studied in four of the volunteers by clone library analysis. Between three and five Bifidobacterium spp. were found in each volunteer. Bifidobacterium adolescentis and Bifidobacterium longum were present in all volunteers, and Bifidobacterium pseudocatenulatum, Bifidobacterium animalis, Bifidobacterium bifidum and Bifidobacterium dentium were also detected. Real-time PCR was employed to quantify the four most prevalent Bifidobacterium spp., B. adolescentis, B. longum, B. pseudocatenulatum and B. bifidum, in ten volunteers carrying detectable levels of bifidobacteria. B. adolescentis showed the strongest response to inulin consumption, increasing from 0·89 to 3·9 % of the total microbiota (P = 0·001). B. bifidum was increased from 0·22 to 0·63 % (P < 0·001) for the five volunteers for whom this species was present.

Current antiretroviral therapy is effective in suppressing but not eliminating HIV-1 infection. Understanding the source of viral persistence is essential for developing strategies to eradicate HIV-1 infection. We therefore investigated the level of plasma HIV-1 RNA in patients with viremia suppressed to less than 50-75 copies/ml on standard protease inhibitor- or non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy using a new, real-time PCR-based assay for HIV-1 RNA with a limit of detection of one copy of HIV-1 RNA. Single copy assay results revealed that >80% of patients on initial antiretroviral therapy for 60 wk had persistent viremia of one copy/ml or more with an overall median of 3.1 copies/ml. The level of viremia correlated with pretherapy plasma HIV-1 RNA but not with the specific treatment regimen. Longitudinal studies revealed no significant decline in the level of viremia between 60 and 110 wk of suppressive antiretroviral therapy. These data suggest that the persistent viremia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy.

Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD. Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data. When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied α4β7 integrin-MADCAM1 axis. Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-α therapy goes through downregulation of certain adhesion molecules.

HIV-tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy. Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear. To determine the effect of prednisone on the inflammatory response in TB-IRIS (antigen-specific effector T cells, cytokines, and chemokines). Blood was taken from participants in a randomized placebo-controlled trial of prednisone for TB-IRIS, at 0, 2, and 4 weeks. Participants received prednisone at a dosage of 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks, or placebo at identical dosages. Analyses included IFN-γ enzyme-linked immunospot (ELISPOT), reverse transcription-polymerase chain reaction on peripheral blood mononuclear cells after restimulation with heat-killed Mycobacterium tuberculosis, Luminex multiplex cytokine analysis of corresponding tissue culture supernatants, and Luminex multiplex cytokine analysis of serum. Fifty-eight participants with TB-IRIS (31 receiving prednisone, 27 receiving placebo) were included. In serum, significant decreases in IL-6, IL-10, IL-12 p40, tumor necrosis factor-α, IFN-γ, and IFN-γ-induced protein-10 concentrations during prednisone, but not placebo, treatment were observed. No differences in ELISPOT responses comparing prednisone and placebo groups were shown in response to ESAT-6 (early secreted antigen target-6), Acr1, Acr2, 38-kD antigen, or heat-killed H37Rv M. tuberculosis. Purified protein derivative ELISPOT responses increased over 4 weeks in the prednisone group and decreased in the placebo group (P = 0.007). The beneficial effects of prednisone in TB-IRIS appear to be mediated via suppression of predominantly proinflammatory cytokine responses of innate immune origin, not via a reduction of the numbers of antigen-specific T cells in peripheral blood.

Objectives The BCG vaccine, widely used in Brazil in new-borns, induces adjuvant protection for several diseases, including childhood virus infections. BCG activates monocytes and innate memory NK cells which are crucial for the antiviral immune response. Therefore, strategies to prevent COVID-19 in health workers (HW) should be carried out to prevent them becoming unwell so that they can continue to work during the pandemic. The hypothesis is that BCG will improve the innate immune response and prevent symptomatic infection or COVID-19 severity. The primary objective is to verify the effectiveness and safety of the BCG vaccine to prevent or reduce incidence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the city of Goiânia (Brazil) among HW previously vaccinated with BCG and also its severity and mortality during the pandemic of the disease. Secondary objectives are to estimate the incidence of COVID-19 among these professionals and the innate immune response elicited to BCG. Trial design This a phase II trial for repositioning BCG as a preventive strategy against COVID-19. The trial is an open-label, parallel-group randomised clinical trial, comparing HW vaccinated with BCG and HW not vaccinated. Participants The trial will recruit 800 HW of Goiânia - Goiás, Brazil to reach a total of 400 HW included after comorbidities questioning and laboratorial evaluation. Eligibility criteria: Any HW presenting BCG vaccination scar with direct contact with suspected COVID-19 patients for at least 8 hours per week, whether in hospital beds, ICU, or in transportation or admission (nurses, doctors, physiotherapists, nutritionists, receptionists, etc.) who have negative IgM and IgG COVID-19 test. Participants with any of the following characteristics will be excluded: - Have had in the last fifteen days any signs or symptoms of virus infection, including COVID-19; - Have had fever in the last fifteen days; - Have been vaccinated fifteen days before the inclusion; - Have a history or confirmation of any immunosuppressive disease such as HIV, presented solid tumour in the last two years or autoimmune diseases; - Are under preventive medication with antibiotics, steroid anti-inflammatories, or chemotherapy; - Have less than 500 neutrophils per mL of blood; - Have previously been diagnosed with tuberculosis; - Are breastfeeding or pregnant; - Are younger than 18 years old; - Are participating as an investigator in this clinical trial. Intervention and comparator HW will be randomized into the BCG vaccinated group or the BCG unvaccinated control group. The BCG vaccinated group will receive in the right arm, intradermally, a one off dose of 0.1 mL corresponding to approximately 2 x10 5 to 8 x10 5 CFU of live, freeze-dried, attenuated BCG Moscow 361-I, Bacillus Calmette Guerin vaccine (Serum Institute of India PVT. LTD.). The unvaccinated control group will not be vaccinated. The HW allocated in both groups will be followed up at specific times points until 180 days post inclusion. The vaccinated and control groups will be compared according to COVID-19 related outcomes. Main outcomes The primary outcomes are the incidence coefficient of infection by SARS-CoV-2 determined by RT-PCR of naso-oropharyngeal swab specimen or rapid lateral flow IgG and IgM test, and presence of general COVID-19 symptoms, disease severity and admission to hospital during the 180 days of follow up. The secondary outcome is the innate immune response elicited 15-20 days after vaccination. Randomisation The vaccine vial contains approximately 10 doses. In order to optimize the vaccine use, the randomisation was performed in blocks of 20 participants using the platform randomization.com [ http://www.jerrydallal.com/random/permute.htm ]. The randomization was prepared before any HW inclusion. The results were printed and inserted in sealed envelopes that were numbered with BCG-001 to BCG-400. The printed results as well the envelopes had the same numbers. At the time of the randomisation, each participant that meets the inclusion criteria will receive a consecutive participant number [BCG-001-BCG-400]. The sealed envelope with the assigned number, blinded to the researchers, will be opened in front of the participant and the arm allocation will be known. Blinding (masking) There is no masking for the participants or for the healthcare providers. The study will be blinded to the laboratory researchers and to those who will be evaluating the outcomes and performing the statistical analyses. In this case, only the participant identification number will be available. Numbers to be randomised (sample size) Four hundred heath workers will be randomised in two groups. Two hundred participants will be vaccinated, and 200 participants will not be vaccinated. Trial Status The protocol approved by the Brazilian Ethical Committee is the seventh version, number CAAE: 31783720.0.0000.5078. The trial has been recruiting since September 20 th , 2020. The clinical trial protocol was registered on August 5 th , 2020. It is estimated that recruitment will finish by March 2021. Trial registration The protocol number was registered on August 5 th , 2020 at REBEC (Registro Brasileiro de Ensaios Clínicos). Register number: RBR-4kjqtg and WHO trial registration number UTN: U1111-1256-3892. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Background The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m 2 ) plus endocrine therapy (ET) in the PACS-01 trial ( J Clin Oncol 2006;24:5664-5671). Methods The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). Results There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p  <  0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p <  0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR ( p  = 0.79). Conclusions After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. Trial registration Not applicable.

This study assessed the effects of a resistance exercise training program on the inflammatory response associated with Toll-like receptor (TLR) 2 and TLR4 signaling pathways in senior participants. Twenty-six healthy subjects (age, 69.5 ± 1.3) were randomized to a training (TG; n  = 16) or a control (CG; n  = 10) group. TG performed an 8-week resistance training program, while CG followed their daily routines. Peripheral blood mononuclear cells were isolated from blood samples obtained before and after the intervention, and levels of proteins involved in the TLR2, TLR4, and myeloid differentiation primary response gene 88 (MyD88)-dependent and MyD88-independent pathways were analyzed. The inflammatory status was evaluated through messenger RNA (mRNA) and protein content of interleukin (IL)-10 and tumor necrosis factor alpha (TNF-α) and plasma levels of C-reactive protein (CRP). After the 8-week resistance training, TLR2 and TLR4 protein expression was reduced in TG. MyD88, p65, phospho-p38, TIR domain-containing adaptor inducing interferon (TRIF), IKKi/IKKε, phospho-interferon regulatory factor (IRF) 3, and phosho-IRF7 were also downregulated in TG after the intervention. The training program induced an increase of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Hsp70 and a reduction of Hsp60. While TNF-α mRNA and protein values remained unchanged in both TG and CG, IL-10 mRNA and protein content were upregulated in TG after the intervention. CRP values decreased in TG only. The increase in Hsp70 negatively correlated with TLR2 and TLR4 downregulation. These data suggest that resistance exercise may represent an effective tool to ameliorate the pro-inflammatory status of old participants through an attenuation of MyD88-dependent and MyD88-independent TLR2 and TLR4 signaling pathways.